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Étude du passage des xénobiotiques dans le lait d'animaux de production par une approche Pharmacocinétique Basée sur la Physiologie (PBPK)

Abstract : Lactation provides essential nutrients and immune cells to the newborn. It also results in the passage of xenobiotics, such as drugs or environmental pollutants, into the milk. Although the passage of xenobiotics in milk is known, both in human medicine (monitoring of nursing mothers) and in veterinary medicine (study of residues and withdrawal time), this complex phenomenon is poorly studied. The work of the thesis focused on a comparative kinetic study of antibiotics in milk of three production animal species (cow, goat, ewe). Four antibiotics (spiramycin, oxytetracycline, marbofloxacin and amoxicillin) were selected because of their distinct physicochemical characteristics and pharmacokinetic properties, thus representing a panel of different kinetic profiles in milk. The objective of the thesis was to study the passage of these different molecules in the milk of three animal species. To achieve this objective, the thesis was carried out in three main steps:(i) Generation of new experimental data. For this purpose, each antibiotic was administered intramuscularly to the three species and individual blood and milk samples were taken for several days after administration. (ii) The development and validation of specific analytical methods for each antibiotic and each matrix (plasma and milk), followed by the determination of the samples. The use of the global approach, based on the accuracy profile, was illustrated by taking the example of spiramycin. Using this approach, a single assay method was developed for the determination of spiramycin and its active metabolite in milk from cows, goats and ewes, thus simplifying and accelerating routine assays in all three milks. (iii) The development of a generic physiologically based pharmacokinetic (PBPK) model to describe the passage of molecules in the milk of production animals. An extensive review of the literature allowed to collect the knowledge on the physiology of the three animal species, the secretion and composition of milk as well as the physicochemical and pharmacokinetic data of the four molecules, necessary for the construction of the model. In vitro experiments on the diffusion of the molecules through a physiological membrane were carried out in collaboration with the University of Utrecht in order to provide information on the membrane permeability parameters. Finally, the PBPK model was applied to the kinetics of oxytetracycline in cow and goat milk and explored the distribution of the antibiotic in the mammary gland and milk, its ionization state as well as its binding to tissue and milk components and its partitioning between the fat and the water phase of the milk. Non-compartmental analyses were performed on the other three antibiotics, allowing comparison of their excretion in milk of the three species, according to their lipophilicity, their ionization and their plasma pharmacokinetic characteristics.Thus, beyond the evaluation of the passage of these four antibiotics in milk, this project aims, thanks to the generic PBPK model, to help predict the pharmacokinetic of xenobiotics in the milk of animals and even lactating women.
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Submitted on : Wednesday, March 30, 2022 - 8:40:20 AM
Last modification on : Thursday, March 31, 2022 - 4:02:26 AM

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Jennifer Tardiveau. Étude du passage des xénobiotiques dans le lait d'animaux de production par une approche Pharmacocinétique Basée sur la Physiologie (PBPK). Chimie analytique. 2021. Français. ⟨tel-03624065⟩



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